Heterocyclic amino substituted heteroaryl fused pyridines; GABA brain receptor ligands

ABSTRACT

Disclosed are compounds of the formula  
                 
 
     or the pharmaceutically acceptable non-toxic salts thereof  
     wherein:  
     n is an integer from 0 to 3;  
     the C ring is aryl or heteroaryl;  
     X is CH, N, or O  
     Z represents an electron pair, hydrogen, or (un)substituted heterocycle, aryl, or amido;  
     W is (un)substituted alkyl, aryl, or heteroaryl;  
     A and B are hydrogen or lower alkyl,  
     which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to heterocyclic amino substitutedheteroaryl fused pyridines, and more specifically to such compounds thatselectively bind to GABAa receptors. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating anxiety, sleep andseizure disorders, and overdoses of benzodiazepine-type drugs, andenhancing alertness. The interaction of heterocyclic amino substitutedheteroaryl fused pyridines of the invention with a GABA binding site,the benzodiazepines (BDZ) receptor, is described. This interactionresults in the pharmacological activities of these compounds.

[0003] 2. Description of the Related Art

[0004] γ-Aminobutyric acid (GABA) is regarded as one of the majorinhibitory amino acid transmitters in the mammalian brain. Over 40 yearshave elapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. GABA mediates many of its actions througha complex of proteins localized both on cell bodies and nerve endings;these are called GABAa receptors. Postsynaptic responses to GABA aremediated through alterations in chloride conductance that generally,although not invariably, lead to hyperpolarization of the cell. Drugsthat interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA.

[0005] The 1,4-Benzodiazepines, such as diazepam, continue to be amongthe most widely used drugs in the world as anxiolytics,sedative-hypnotics, muscle relaxants, and anticonvulsants. A number ofthese compounds are extremely potent drugs; such potency indicates asite of action with a high affinity and specificity for individualreceptors. Early electrophysiological studies indicated that a majoraction of benzodiazepines was enhancement of GABAergic inhibition.Presently, those compounds possessing activity similar to thebenzodiazepines are called agonists. Compounds possessing activityopposite to benzodiazepines are called inverse agonists, and thecompounds blocking both types of activity have been termed antagonists.

[0006] The GABAa receptor subunits have been cloned from bovine andhuman cDNA libraries (Schoenfield et al., 1988; Duman et al., 1989). Anumber of distinct cDNAs were identified as subunits of the GABAareceptor complex by cloning and expression. These are categorized intoα, β, γ, δ, ε, and provide a molecular basis for the GABAa receptorheterogeneity and distinctive regional pharmacology (Shivvers et al.,1980; Levitan et al., 1989). The γ subunit appears to enable drugs likebenzodiazepines to modify the GABA responses (Pritchett et al., 1989).The presence of low Hill coefficients in the binding of ligands to theGABAa receptor indicates unique profiles of subtype specificpharmacological action.

[0007] With the discovery of the “receptor” for the benzodiazepines andthe subsequent definition of the nature of the interaction between GABAand the benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior. Depending on the mode ofinteraction, these compounds are capable of producing a spectrum ofactivities (either sedative, anxiolytic, and anticonvulsant, orwakefulness, seizures, and anxiety).

SUMMARY OF THE INVENTION

[0008] This invention provides novel compounds of Formula I whichinteract with a GABAa binding site, the benzodiazepine receptor.

[0009] The invention provides pharmaceutical compositions comprisingcompounds of Formula I. The invention also provides compounds useful inthe diagnosis and treatment of anxiety, sleep and seizure disorders,overdose with benzodiazepine drugs and for enhancement of memory.Accordingly, a broad embodiment of the invention is directed tocompounds of general Formula I:

[0010] wherein:

[0011] the C ring represents a thiophene, pyridine, pyrazine,pyridazine, or pyrimidine ring, each of which is optionally mono- ordisubstituted with lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

[0012] n is 0 or an integer of from 1-3;

[0013] X is CH, nitrogen, or oxygen;

[0014] Z is an electron pair when X is oxygen;

[0015] Z is hydrogen;

[0016] Z is aryl or heteroaryl, each of which is optionally substitutedwith one, two or three groups independently selected from lower alkyl,lower alkoxy, amino, mono- or di(C₁-C₆)alkylamino, or halogen; or

[0017] Z is

[0018] where

[0019] Y is oxygen or sulfur;

[0020] R is lower alkyl, hydroxy, lower alkoxy, hydroxyalkyl, oraminoalkyl, or mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl;

[0021] R is aryl or heteroaryl each of which is mono or disubstitutedindependently with halogen, thio, hydroxyl, lower alkyl, lower alkoxy,amino or mono- or di(C₁-C₆)alkylamino;

[0022] R is amino, optionally substituted with one or two groupsindependently selected from

[0023] lower alkyl, hydroxyalkyl, C₃-C₇ cycloalkyl, alkoxyalkyl,aminoalkyl, haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;

[0024] heteroaryl, arylalkyl or heteroarylalkyl, optionally substitutedwith one or two groups independently selected from halogen, thio,hydroxyl, lower alkyl, lower alkoxy, or amino; or

[0025] a C₃-C₇ carbocyclic group having, where up to two of which atomsof the carbocyclic group are optionally hetero atoms selected fromoxygen and nitrogen and where any atom of the carbocyclic group isoptionally substituted with halogen, lower alkyl or lower alkoxy; or

[0026] R is a carbocyclic group having from 3-7 members, where up tothree of which members are optionally hetero atoms selected from oxygenand nitrogen and where any member of the carbocyclic group is optionallysubstituted with halogen, lower alkyl, or lower alkoxy;

[0027] A and B are the same or different and represent hydrogen or loweralkyl; and

[0028] W is aryl or heteroaryl, each of which may be mono-, or di-, ortrisubstituted independently with halogen, hydroxyl, lower alkyl, loweralkoxy, amino, mono- or di(C₁-C₆)alkylamino, trifluoromethyl or nitro.

[0029] These compounds are highly selective agonists, antagonists orinverse agonists for GABAa brain receptors or prodrugs of agonists,antagonists or inverse agonists for GABAa brain receptors. In otherwords, while the compounds of the invention all interact with GABAabrain receptors, they do not display identical physiological activity.Thus, these compounds are useful in the diagnosis and treatment ofanxiety, sleep and seizure disorders, overdose with benzodiazepine drugsand for enhancement of memory. For example, these compounds can be usedto treat overdoses of benzodiazepine-type drugs as they wouldcompetitively bind to the benzodiazepine receptor.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The novel compounds encompassed by the instant invention can bedescribed by general Formula I set forth above or the pharmaceuticallyacceptable non-toxic salts thereof.

[0031] In addition, the present invention also encompasses compounds ofFormula IIa and IIb

[0032] wherein A, B, W, X, Z, and n are as defined above for Formula I;and

[0033] R_(a) and R_(b) independently represent hydrogen, lower alkyl,C₁-C₆ alkoxy, hydroxy, halogen, amino, mono- or di(C₁-C₆)alkylamino, ortrifluoromethyl.

[0034] Preferred compounds of Formula IIa and IIb are R_(a) and R_(b)are hydrogen, and a where W is phenyl or 2-, 3-, or 4-pyridyl, each ofwhich is optionally mono or disubstituted independently with halogen,hydroxyl, lower alkyl, or lower alkoxy. Other preferred compounds ofFormula IIa and IIb are those where X is CH and Z is or 2-imidazolyl, or1,2,4-triazol-3-yl,

[0035] Other preferred compounds of the invention are those of FormulaII where n is 2 or 3.

[0036] Other preferred compounds of Formula IIa and IIb are where A andB are hydrogen or methyl.

[0037] Preferred Z groups in Formulae IIa and IIb include Z-1, Z-2, Z-3,Z-4, Z-5, Z-6, Z-7, Z-8, and Z-9 groups.

[0038] where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl,2-, 3-, or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, or 2- or 3-tetrahydrofuranyl(C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl-(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-1 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

[0039] where E is a bond or C₁-C₆ alkylene, each of Rp and R_(p)′ areindependently hydroxy, halogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy. PreferredR_(p) groups are fluoro, more preferably 4-fluoro, and chloro. PreferredR_(p)′ groups are hydrogen, C₁-C₂ alkoxy, C₁-C₂ alkyl, fluoro, morepreferably 4-fluoro, and chloro. Preferred E groups are a bond and C₂alkylene.

[0040] where G is 2-, 3-, or 4-pyridyl, each of which is optionallymono- or disubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen.

[0041] where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl,2-, 3-, or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆) alkyl, 2-, or 3-tetrahydrofuranyl (C₁-C₆) alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-6 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

[0042] where R_(e) is hydrogen or C₁-C₆ alkyl. Preferred R_(e) groups inZ-7 are hydrogen atoms.

[0043] where each R_(e) is independently hydrogen or C₁-C₆ alkyl.Preferred R_(e) groups in Z-8 are hydrogen and methyl.

[0044] where R is C₁-C₆ alkyl.

[0045] The present invention also encompasses compounds of Formula IIIaand Formula IIIb:

[0046] wherein W, X and Z are as defined above for Formula I; and

[0047] R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen,amino, mono- or di(C₁-C₆)alkylamino, or trifluoromethyl.

[0048] Preferred compounds of Formula IIIa and IIIb are where W isphenyl or 2-, 3-, or 4-pyridyl, each of which is optionally mono ordisubstituted independently with halogen, hydroxyl, lower alkyl, orlower alkoxy.

[0049] Preferred Z groups in Formulae IIIa and IIIb include Z-1, Z-2,Z-3, Z-4, Z-5, Z-6, Z-7, Z-8, and Z-9 groups.

[0050] where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl,2-, 3-, or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, or 2- or 3-tetrahydrofuranyl(C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl-(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-1 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

[0051] where E is a bond or C₁-C₆ alkylene, each of R_(p) and R_(p)′ areindependently hydroxy, halogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy. PreferredR_(p) groups are fluoro, more preferably 4-fluoro, and chloro. PreferredR_(p)′ groups are hydrogen, C₁-C₂ alkoxy, C₁-C₂ alkyl, fluoro, morepreferably 4-fluoro, and chloro. Preferred E groups are a bond and C₂alkylene.

[0052] where G is 2-, 3-, or 4-pyridyl, each of which is optionallymono- or disubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen.

[0053] where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl,2-, 3-, or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, 2-, or 3-tetrahydrofuranyl (C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-6 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

[0054] where R_(e) is hydrogen or C₁-C₆ alkyl. Preferred R_(e) groups inZ-7 are hydrogen atoms.

[0055] where each R_(e) is independently hydrogen or C₁-C₆ alkyl.Preferred R_(e) groups in Z-8 are hydrogen and methyl.

[0056] where R is C₁-C₆ alkyl.

[0057] The present invention also encompasses compounds of Formula IV:

[0058] wherein W, X, and Z are as defined above in Formula I; and

[0059] A, B, C, and D are independently CR₁ or nitrogen, provided thatno more than two of A, B, C, and D are nitrogen simultaneously; and

[0060] R₁ is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy,hydroxyalkyl, aminoalkyl, alkoxyalkyl, thio, or arylalkyl.

[0061] Preferred compounds of Formula IV are where W is phenyl or 2-,3-, or 4-pyridyl each of which is optionally mono or disubstitutedindependently with halogen, hydroxyl, lower alkyl, or lower alkoxy.

[0062] Still other preferred compounds of Formula IV are those where Ais nitrogen and B, C, and D are hydrogen.

[0063] Preferred Z groups in Formula IV include Z-1, Z-2, Z-3, Z-4, Z-5,Z-6, Z-7, Z-8, and Z-9 groups.

[0064] where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl,2-, 3-, or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, or 2- or 3-tetrahydrofuranyl(C₁-C₆)alkyl. PreferredC₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl.Preferred tetrahydrofuranyl-(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-1 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

[0065] where E is a bond or C₁-C₆ alkylene, each of R_(p) and R_(p)′ areindependently hydroxy, halogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy. PreferredR_(p) groups are fluoro, more preferably 4-fluoro, and chloro. PreferredR_(p)′ groups are hydrogen, C₁-C₂ alkoxy, C₁-C₂ alkyl, fluoro, morepreferably 4-fluoro, and chloro. Preferred E groups are a bond and C₂alkylene.

[0066] where G is 2-, 3-, or 4-pyridyl, each of which is optionallymono- or disubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen.

[0067] where R_(z) and R_(y) are independently hydrogen, C₁-C₆ alkyl,2-, 3-, or 4-pyridylmethyl, C₃-C₇, preferably C₄-C₆, cycloalkyl, C₁-C₆alkoxy (C₁-C₆) alkyl, 2-, or 3-tetrahydrofuranyl (C₁-C₆) alkyl.Preferred C₁-C₆ alkoxy(C₁-C₆)alkyl groups are 2-methoxyethyl and2-ethoxyethyl. Preferred tetrahydrofuranyl(C₁-C₆)alkyl groups aretetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-6 groups arethose where one and only one of R_(z) and R_(y) is hydrogen.

[0068] where R_(e) is hydrogen or C₁-C₆ alkyl. Preferred R_(e) groups inZ-7 are hydrogen atoms.

[0069] where each R_(e) is independently hydrogen or C₁-C₆ alkyl.Preferred R_(e) groups in Z-8 are hydrogen and methyl.

[0070] where R is C₁-C₆ alkyl.

[0071] Preferred compounds of the invention are encompassed by thefollowing formulae:

[0072] where W, X, and Y are as defined above in Formula I;

[0073] R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen,amino, mono- or di(C₁-C₆)alkylamino, or trifluoromethyl; and

[0074] R₂ and R₃ are the same or different and represent

[0075] hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalky, or amidoalkyl;

[0076] aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which maybe mono or disubstituted independently on the aryl group with halogen,thio, hydroxyl, lower alkyl, lower alkoxy, or amino; or

[0077] a C₃-C₇ carbocyclic or C₃-C₇ carbocyclic (C₁-C₆) alkyl grouphaving from 3-7 members, where up to two of which members are optionallyhetero atoms selected from oxygen and nitrogen and where any member ofthe carbocyclic group is optionally substituted with halogen, loweralkyl or lower alkoxy.

[0078] More preferred compounds of Formula Va and Vb are those where R₂is hydrogen and where W is aryl or heteroaryl mono or disubstitutedindependently with halogen, hydroxyl, lower alkyl, or lower alkoxy.

[0079] Other preferred compounds are represented by Formula VI.

[0080] where W, and X are as defined above in Formula I and wherein:

[0081] A, B, C, and D are independently CR₁ or nitrogen, provided thatat least one but not more than two of A, B, C, and D are nitrogensimultaneously;

[0082] R₁ is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy,hydroxyalkyl, aminoalkyl, alkoxyalkyl, thio, or arylalkyl; and

[0083] R₂ and R₃ are the same or different and represent

[0084] hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalky, or amidoalkyl;

[0085] aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which maybe mono or disubstituted independently on the aryl group with halogen,thio, hydroxyl, lower alkyl, lower alkoxy, or amino, or

[0086] a carbocyclic or carbocyclic(C₁-C₆)alkyl group having from 3-7members in the carbocyclic portion, where up to two of which members areoptionally hetero atoms selected from oxygen and nitrogen and where anymember of the carbocyclic group is optionally substituted with halogen,lower alkyl or lower alkoxy.

[0087] More preferred compounds of Formula VI are where W is phenyl or2-, 3-, or 4-pyridyl each of which is optionally mono or disubstitutedindependently with halogen, hydroxyl, lower alkyl, or lower alkoxy;where A is nitrogen and B, C, and D are hydrogen; and where R₂ ishydrogen and R₃ is hydrogen or lower alkyl.

[0088] Still other preferred compounds of the invention are representedby Formula VIIa and VIIb.

[0089] where W and X are as above in Formula I and wherein

[0090] n is the integer 2 or 3;

[0091] Z is an electron pair when X is oxygen;

[0092] Z is hydrogen;

[0093] Z is aryl optionally substituted with one or two groups selectedfrom lower alkyl, lower alkoxy, or halogen; or

[0094] Z is

[0095] where

[0096] Y is oxygen or sulfur;

[0097] R is

[0098] amino, optionally substituted with one or two groups selectedfrom lower alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy,aminoalkyl, amidoalkyl, heteroaryl.

[0099] More preferred compounds of Formula VIIa and VIIb are where whereY is oxygen and W is aryl or heteroaryl mono or disubstitutedindependently with halogen, hydroxyl, lower alkyl, or lower alkoxy.

[0100] The present invention also encompasses compounds of Formula VIIIaand Formula VIIIb:

[0101] wherein W and X are as defined above for Formula I;

[0102] R_(x) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen,amino, mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

[0103] A is nitrogen or CH; and

[0104] R_(x) is hydrogen, lower alkyl, hydroxy, lower alkoxy,hydroxyalkyl, or aminoalkyl, or mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

[0105] Preferred compounds of Formula VIIIa and VIIIb are where W isphenyl or 2-, 3-, or 4-pyridyl, each of which is optionally mono ordisubstituted independently with halogen, hydroxyl, lower alkyl, orlower alkoxy. Other preferred compounds of Formulae VIIIa and b arethose where X is CH and A is CH. More preferred compounds of FormulaVIIIa and b where A is CH are those where R_(x) is hydrogen, methyl orethyl. Particularly preferred compounds of Formulae VIIIa and b where Ais CH are those where W is phenyl optionally substituted with one or twogroups selected from halogen, preferably fluoro and chloro, methyl,ethyl, or amino.

[0106] Still other preferred compounds of Formulae VIIIa and b are thosewhere X is CH and A is nitrogen. More preferred compounds of FormulaVIIIa and b where A is nitrogen are those where R_(x) is hydrogen,methyl or ethyl. Particularly preferred compounds of Formulae VIIIa andb where A is nitrogen are those where W is phenyl optionally substitutedwith one or two groups selected from halogen, preferably fluoro andchloro, methyl, ethyl, or amino.

[0107] By “alkyl” and “lower alkyl” in the present invention is meantstraight or branched chain alkyl groups having 1-6 carbon atoms, suchas, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl.

[0108] By “alkoxy” and “lower alkoxy” in the present invention is meantstraight or branched chain alkoxy groups having 1-6 carbon atoms, suchas, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy,hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

[0109] By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine. Preferred halogens are fluorine, bromine,and chlorine.

[0110] By heteroaryl is meant one or more aromatic ring systems of 5-,6-, or 7-membered rings containing at least one and up to fourheteroatoms selected from nitrogen, oxygen, or sulfur. Such heteroarylgroups include, for example, thienyl, furanyl, thiazolyl, imidazolyl,(is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, napthyridinyl,benzimidazolyl, benzoxazolyl. Preferred heteroaryl groups arepyrimidinyl, pyridyl, imidazolyl, naphthyridinyl, and benzimidazolylgroups that are optionally substituted as described herein.

[0111] The heteroaryl groups of the invention may be substituted with upto four groups selected from, for example, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, mono- or di (C₁-C₆)alkylamino (C₁-C₆) alkyl, halogen, thio, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, C₃-C₇ cycloalkyl, alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, and amidoalkyl. Other heteroaryl substituents include,for example, phenyl, pyridyl, pyrimidiyl, imidazolyl, morpholinyl,piperidinyl, piperazinyl, pyrrolyl, and pyrrolidinyl.

[0112] By 1H-1,4-Diazepine is meant the structure

[0113] By aryl is meant an aromatic carbocyclic group having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy. Preferred aryl groups are phenyl andnapthyl groups that are optionally substituted as described herein.

[0114] The aryl groups of the invention may be substituted with up tofour groups selected from, for example, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, mono- or di (C₁-C₆)alkylamino(C₁-C₆) alkyl, halogen, thio, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, C₁-C₇ cycloalkyl, alkoxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, and amidoalkyl. Other aryl substituents include, forexample, phenyl, pyridyl, pyrimidiyl, imidazolyl, morpholinyl,piperidinyl, piperazinyl, pyrrolyl, and pyrrolidinyl.

[0115] Representative C₃-C₇ carbocyclic or C₃-C₇ carbocyclic(C₁-C₆)alkylgroups that include one or two oxygen or nitrogen atoms are, forexample, morpholino, pyrrolo, imidazolyl, piperidinyl, piperazinyl,pyrazinyl, pyranyl, tetrahydropyanyl, pyrrolidinyl, 1H-1,4-diazepinyl,and pyrrolinyl. These groups are optionally substituted with one or twogroups, preferably one group, selected from halogen, lower alkyl andlower alkoxy.

[0116] Representative compounds of the invention are shown below inTable 1. TABLE 1

[0117] Representative compounds of the present invention, which areencompassed by Formula I, include, but are not limited to the compoundsin Table I and their pharmaceutically acceptable acid and base additionsalts. In addition, if the compound of the invention is obtained as anacid addition salt, the free base can be obtained by basifying asolution of the acid salt. Conversely, if the product is a free base, anaddition salt, particularly a pharmaceutically acceptable addition salt,may be produced by dissolving the free base in a suitable organicsolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basecompounds.

[0118] Non-toxic pharmaceutically acceptable salts include salts ofacids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic,formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric,tartaric, maleic, hydroiodic, alkanoic such as acetic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

[0119] The present invention also encompasses the acylated prodrugs ofthe compounds of Formula I. Those skilled in the art will recognizevarious synthetic methodologies which may be employed to preparenon-toxic pharmaceutically acceptable addition salts and acylatedprodrugs of the compounds encompassed by Formula I.

[0120] The compounds of Formula I and their salts are suitable for thediagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive andseizure disorders, and overdose with benzodiazepine drugs and forenhancement of alertness, both in human and non-human animals anddomestic pets, especially dogs and cats and farm animals such as sheep,swine and cattle.

[0121] The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

[0122] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

[0123] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0124] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0125] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide palatableoral preparations. These compositions may be preserved by the additionof an anti-oxidant such as ascorbic acid.

[0126] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0127] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

[0128] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitor or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also besterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0129] The compounds of general Formula I may also be administered inthe form of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0130] Compounds of general Formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0131] Dosage levels of the order of from about 0.1 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

[0132] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0133] For administration to non-human animals, the composition may alsobe added to the animal feed or drinking water. It will be convenient toformulate these animal feed and drinking water compositions with amullet-dose of the drug so that the animal takes in an appropriatequantity of the composition along with its diet. It will also beconvenient to present the composition as a premix for addition to thefeed or drinking water.

[0134] The compounds of the invention may be prepared using thesynthetic routes outlined in the following schemes.

[0135] where A, B, the C ring, W, Y, R, R₂, R₃ and n are as definedabove in Formula I.

[0136] Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the present invention, as demonstrated by thefollowing examples. For example, certain groups, e.g., nitrogen andhydroxy, may require protection during the synthesis.

[0137] As shown in Scheme I, an aniline is reacted with a suitableβ-keto ester in the presence of an acid, such as, for example,P-toluenesulfonic acid, to form a 4-hydroxypyridine which issubsequently converted to the 4-chloropyridine upon treatment with anucleophilic halogenating reagent such phosphorus oxychloride. Theresulting chloride is reacted with the desired 1,4-diheterocarbocycle,such as a piperazine or 1,4-diazaperhydropine at elevated temperaturesto form the N-alkylated product. The piperdine can then be furtheralkylated with a desired isocyanate or isothiocyanate, such as, forexample, methyl isocyanate, to form the target compound.

[0138] As shown in Scheme II, a 4-chloropyridine is reacted with areagent such as ethyl 4-piperdinecarboxylate at elevated temperatures toform the N-alkylated ester. The ester is treated with an amine, such asmethylamine, in the presence of a base such as sodium hydroxide to formthe resulting amide.

[0139] The disclosures in this application of all articles andreferences, including patents, are incorporated herein by reference.

[0140] The invention is illustrated further by the following exampleswhich are not to be construed as limiting the invention in scope orspirit to the specific procedures described in them.

[0141] The starting materials and various intermediates may be obtainedfrom commercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.

[0142] Representative examples of methods for preparing intermediates ofthe invention are set forth below.

EXAMPLE 1 1. 5-(4-Fluorophenyl)-thieno[3,2-b]pyridin-7-ol

[0143]

[0144] A mixture of 3-amino-2-thiophenecarboxylic acid (8 g, 49 mmol),ethyl 4-fluorobenzoylacetate (9.6 g, 49 mmol), and p-toluenesulfonicacid monohydrate (0.2 g, 1 mmol) in toluene (100 mL) is refluxed for 20hours with a Dean-Stark water trap to remove produced water. The mixtureis cooled to room temperature. The resulting precipitate is filtered andwashed with diethyl ether. The solid is dissolved in diphenyl ether (80mL) and heated at 220° C. for 2 hours. The reaction solution is thencooled to room temperature and diluted with diethyl ether; theprecipitate is filtered and washed with diethyl ether to give5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (2 g, 17% yield) as browncrystalline needles, m.p. 316-318° C.

2. 7-Chloro-5-(4-fluorophenyl)thieno[3.2-b]pyridine

[0145]

[0146] A solution of 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (1.6g) in phosphorus oxychloride (50 mL) is refluxed for 3 hours. After theexcess amount of phosphorus oxychloride is removed under vacuum, theresidue is treated with ethyl acetate (20 mL) and NaOH (2N, 20 mL). Themixture is then extracted with ethyl acetate (3×20 mL). The combindedorganic layers are washed with brine and dried over MgSO₄. Evaporationof the solvent affords 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine(1.5 g, 88% yield) as a white solid, m.p. 119-121° C.

3.1-(5-(4-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide

[0147] A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (68mg, 0.26 mmole), isonipecotamide (66 mg, 0.52 mmole), and sodium acetate(21 mg, 0.26) in 1-methyl-2-pyrrolidone (3 mL) is stirred and heated inan oil bath at 160° C. for 4 hours. The reaction mixture is then cooledand diluted with EtAc (15 mL), transferred to a separatory funnel, andwashed with water (3×15 mL). The organic layer is dried over sodiumsulfate and concentrated. The residue is recrystalized with ethylacetate to give1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide(55 mg, 60% yield) as a white solid. This material is dissolved in ethylacetate and HCl saturated ethyl acetate (2 mL) is added. The solution isconcentrated to afford the HCl salt as a greasy oil.1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 3) is precipitated out of an ether solution,collected by filtration, washed with ether, and dried in vacuo to affordthe final product. m.p. 303-305° C. (dec).

EXAMPLE 2 1. 4-Chloro-6-phenylthieno[2,3-b]pyridine

[0148]

[0149] A mixture of 3-aminothiophene (4 g, 0.04 mole), ethylbenzoylacetate (11 mL, 0.06 mole), toluene (100 mL), and p-toluenesulfonic acid monohydrate (300 mg) is stirred and heated under refluxwith a Dean-Stark water trap at 120° C. for 16 hours. The reactionmixture is concentrated, and diphenyl ether (30 mL) is added. Afterheating at 240° C. for 1 hour, the reaction mixture was allowed to coolto room temperature. The reaction mixture is diluted with hexane, andthe semi-solid collected is then purified by short silica gel column(CH₂Cl₂/MeOH/NH₄OH: 10:1:0.1). The resulting product,4-hydroxy-6-phenyl-thieno[2,3-b]pyridine, is treated with phosphorusoxychloride (30 mL) and heated under reflux for 3 hours. This mixture iscooled to room temperature, poured over ice, neutralized with 10 Nsodium hydyoxide, and extracted with methylene chloride (3×20 mL). Thecombined organic layers are dried over sodium sulfate and concentratedin vacuo. The residue is purified by chromatography to give4-chloro-6-phenylthieno[2,3-b]pyridine as a yellowish solid (1.1 g, 11%total yield), m.p. 83-85° C.

2. Ethyl 1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylate

[0150]

[0151] A mixture of 4-chloro-6-phenyl-thieno[2,3-b]pyridine (200 mg,0.82 mmole) and ethyl isonipecotate (5 mL) is stirred and heated in anoil bath at 170° C. for 6 hours. The reaction mixture is cooled andpurified on a preparative tlc plate to give ethyl1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylate (100 mg,33% yield) as a colorless oil.

EXAMPLE 3 N-Ethyl 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-Dipiperidinecarboxamide

[0152] A solution of1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylic acid ethylester (50 mg, 0.14 mmole), ethylamine (2 mL), and a catalytic amount ofsodium cynide in MeOH (10 mL) is heated in a sealed tube at 70° C. oilbath for 48 hours. The solvent is removed on rotary-evaporator. Theresulting residue is purified on a preparative tlc plate to give N-Ethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4 piperidinecarboxamide (20 mg,39% yield) as a colorless oil. This material is dissolved in ethylacetate (1 mL), diluted with HCl saturated ethyl acetate (2 mL), andconcentrated to afford N-ethyl1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamidehydrochloride (compound 1, 26 mg) as greasy oil. The salt is solidifiedwith ether, collected by filtration, washed with ether, and dried invacuo. m.p. >270° C. (dec).

EXAMPLE 4 1. 1-(5-Phenylthieno[3 2-b]pyridin-7-yl)-4-piperazine

[0153]

[0154] A reaction mixture of 7-chloro-5-phenylthieno[3,2-b]pyridine (200mg, 0.82 mmole), piperazine (100 mg, 1.19 mmole) and phenol (1 g) isheated under N₂ at 160° C. oil bath for 3 hours. The mixture is cooleddown to room temperature, dilutied with EtAc (15 mL), transferred to aseparatory funnel, and extracted with 5% HCl solution (3×15 mL). Thecombined acidic extracts are basified using concentrated NH₄OH solutionand then extracted with CH₂Cl₂ (3×15 mL). The combined organic layersare dried over soduim sulfate and concentrated, and the crude residue ispurified on a preparative tlc plate to give1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperazine (90 mg, 37% yield) asa yellowish oil.

2. N-Methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide

[0155] A reaction solution of1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazine (120 mg, 0.41 mmole)and methyl isocynate (0.5 mL) in toluene (10 mL) is heated in a 120° C.oil bath for 1 hour. The resulting solution is cooled down to roomtemperature and concentrated. The crude residue is purified on apreparative tlc plate to give N-Methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide (100 mg,69% yield) as a colorless oil. This material is dissolved in 1 mL ethylacetate. Ethyl acetate saturated with HCl (2 mL) is added and thesolution is then concentrated to afford 105 mg of N-methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 2) as a greasy oil. The salt is solidified withether, collected by filtration, washed with ether, and dried in vacuo.m.p. 185-190° C.

EXAMPLE 5 7-Chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine

[0156] A solution of 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (1.6g) in phosphorus oxychloride (50 mL) is refluxed for 3 hours. After theexcess phosphorus oxychloride is removed under vacuum, the residue istreated with ethyl acetate (20 mL), and NaOH (2N, 20 mL). The mixture isextracted with ethyl acetate (3×20 mL) and the combined organic layersare washed with brine and dried over MgSO₄. Evaporation of the solventgives 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (1.5 g, 88%yield) as a white solid, m.p. 119-121° C.

EXAMPLE 6 5-(4-Fluorophenyl)-7-[4-(1H-imidazol-2-yl)-1-piperidinylthieno[3,2-b]pyridine

[0157] A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine(146 mg, 0.53 mmole), 4-(1H-imidazol-2-yl)piperidine hydrochloride (SeeU.S. Pat. No. 4,431,653) (100 mg, 0.53 mmole) and sodium acetate (50 mg)in ethylene glycol (10 ml) is stirred and heated at 160° C. for 16hours. It is then cooled, diluted with ethylacetate (15 mL), and washedwith water (3×15 mL). The organic layer is dried over sodium sulfate,and concentrated. The residue is purified by preparative tlc plate togive 5-(4-fluorophenyl)-7-[4-(1H-imidazol-2-yl)-1-piperidinylthieno[3,2-b]pyridine (36 mg, 18% yield) as a white solid, m.p. 95° C.(compound 63).

EXAMPLE 71-(5-(4-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide

[0158] A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (68mg, 0.26 mmole), isonipecotamide (66 mg, 0.52 mmole), and sodium acetate(21 mg, 0.26 mmole) in 1-methyl-2-pyrrolidone (3 mL) is stirred andheated in an oil bath at 160° C. for 4 hours. The mixture is thencooled, diluted with ethyl acetate (15 mL), and washed with water (3×15mL). The organic layer is dried over sodium sulfate, and concentrated.The residue is recrystalized from ethyl acetate to give1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide(Compound 64, 55 mg, 60% yield) as a white solid product (m.p. 251°C.-253° C.).

EXAMPLE 85-(4-Fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridine

[0159] A suspension of1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide(100 mg, 0.32 mmole) in phosphorus oxochloride (5 mL) is refluxed for0.5 hours. After the excess phosphorus oxychloride is removed undervacuum, the residue is treated with ethyl acetate (5 mL), and ice-water(10 mL). The resulting mixture is subsequently extracted with ethylacetate (3×10 mL) and the combined organic layers are washed with brine,dried over sodium sulfate, and concentrated. The residue is thendissolved in toluene (5 mL), then formic hydrazid (100 mg, 1.7 mmole),and formic acid (0.05 mL) are added. The reaction mixture is refluxedfor 16 hours, cooled, diluted with ethyl acetate (15 mL), and washedwith water (3×15 mL). The organic layer is dried over sodium sulfate,and concentrated.

[0160] The residue is purified by preparative tlc plate to give5-(4-fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridine(7 mg, 6% yield) as a white solid. This material is dissolved in ethylacetate (1 mL), saturated with HCl (2 mL), and then concentrated toafford5-(4-fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridinehydrochloride (compound 65) as greasy oil.

[0161] The salt is solidified with ether, collected by filtration,washed with ether and dried in vacuo, m.p. >300 ° C. (dec).

EXAMPLE 9

[0162] The following compounds were prepared essentially according tothe procedures set forth in Examples 1-8:

[0163] a)1-(5-(2-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide(compound 4), m.p. 194-195° C.

[0164] b)N-4-Picolyl-1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidedihydrochloride (compound 5), m.p. 176-178° C. (dec).

[0165] c) N-(2-Hydroxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 6), m.p. >220° C. (dec).

[0166] d)4-Fluorophenylcarbonyl-1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl))-4-piperazinehydrochloride (compound 7), m.p. >174° C. (dec).

[0167] e)N-Methylhexahydro-4-(5-phenylthieno[3,2-b]pyridin-7-yl)-(1H-1,4-diazepine)(compound 8), m.p. >220° C. (dec).

[0168] f) 4-(5-Phenylthieno[3,2-b]pyridin-7-yl)morpholine hydrochloride(compound 9), m.p. 195-198° C.

[0169] g)1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-[1H-1,4-diazepine]dihydrochloride(compound 10), m.p. >255° C. (dec).

[0170] h)N-Ethylhexahydro-4-(5-phenylthieno[3,2-b]pyridin-7-yl)-(1H-1,4-diazepine)-1-carboxamidedihydrochloride (compound 11), m.p. >180° C. (dec).

[0171] i) N-Ethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 12), m.p. >240° C. (dec).

[0172] j)4-Pyridinylcarbonyl-1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl))-4-piperazinehydrochloride (compound 13), m.p. 215-217° C.

[0173] k) N-Ethyl1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 14), m.p. >198-201° C.

[0174] l) N-n-Propyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 15), m.p. >130° C. (dec).

[0175] m) N-i-Propyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 16), m.p. 127-129° C. (dec).

[0176] n) N-n-Butyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 17), m.p. >93° C. (dec).

[0177] o) N-(3-Chloro-n-Propyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 18), m.p. 235-238° C. (dec).

[0178] p) N-Ethyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamidehydrochloride (compound 19), m.p. >147° C. (dec).

[0179] q) N-Ethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarbothioamidehydrochloride (compound 20), m.p. >° C. (dec).

[0180] r) 1-(2-Phenyl-1,5-naphthyridin-4-yl)-4-piperidinecarboxylic acidethyl ester hydrochloride (compound 21), m.p. >180° C. (dec).

[0181] s) N-Ethyl1-(2-phenyl-1,5-naphthyridin-4-yl)-4-piperidinecarboxamide hydrochloride(compound 22), m.p. >210° C. (dec).

[0182] t) N-Methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 23), m.p. >260° C. (dec).

[0183] u) N-Propyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 24), m.p. 159-160° C. (dec).

[0184] v) 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 25), m.p. ° C. (dec).

[0185] w) N-t-Butyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 26), m.p. 270-272° C. (dec).

[0186] x) N-n-Butyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 27), m.p. 170-172° C. (dec).

[0187] y) N-Cyclopropyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 28), m.p. 199-201° C. (dec).

[0188] z) N-Cyclopentyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 29), m.p. 179-181° C. (dec).

[0189] aa) N-(2-Aminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 30), m.p. 176-178° C. (dec).

[0190] bb) N-(2-Ethylaminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 31), m.p. >95° C. (dec).

[0191] cc) N-(2-Dimethylaminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 32), m.p. >150° C. (dec).

[0192] dd) N-Glycinamidyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 33), m.p. 158-160° C. (dec).

[0193] ee) N-(2-Hydroxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 34), m.p. >220° C. (dec).

[0194] ff) N-(2-Methoxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 35), m.p. 157-160° C. (dec).

[0195] gg) N-(3-Methoxypropyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 36), m.p. 147-149° C. (dec).

[0196] hh) N-Benzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 37), m.p. 163-165° C. (dec).

[0197] ii) N-2-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 38), m.p. 164-166° C. (dec).

[0198] jj) N-3-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 39), m.p. 236-238° C. (dec).

[0199] kk) N-4-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 40), m.p. 190-192° C. (dec).

[0200] ll) N-4-Methylbenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 41), m.p. 177-178° C. (dec).

[0201] mm) N-4-Ethoxybenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 42), m.p. >° C. (dec).

[0202] nn) N-4-Pyridylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 43), m.p. >° C. (dec).

[0203] oo) N-2-Thiophenylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 44), m.p. >230° C. (dec).

[0204] pp) N-2-Tetrahydrofuranylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 45), m.p. >210° C. (dec).

[0205] qq) 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylicacid ethyl ester hydrochloride (compound 46), m.p. >° C. (dec).

[0206] rr) 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylicacid hydrochloride (compound 47), m.p. >° C. (dec).

[0207] ss)1-(5-(3-Methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 48), m.p. 133-135° C. (dec).

[0208] tt) N-Ethyl1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 49), m.p. >230° C. (dec).

[0209] uu)1-(5-(4-Ethoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 50), m.p. 211-213° C. (dec).

[0210] vv) N-2-Pyridinylmethyl1-(5-(4-ethoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 51), m.p. 178-180° C. (dec).

[0211] ww)1-(5-(4-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 52), m.p. >303° C. (dec).

[0212] xx) N-Methyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 53), m.p. >° C. (dec).

[0213] yy) N-Ethyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 54), m.p. 220-222° C. (dec).

[0214] zz) N-Propyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 55), m.p. 207-209° C. (dec).

[0215] aaa) N-(2-Aminoethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 56), m.p. 115-118° C. (dec).

[0216] bbb) N-(2-Dimethylaminoethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 57), m.p. 180-182° C. (dec).

[0217] ccc) N-(2-Hydroxyethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 58), m.p. 198-200° C. (dec).

[0218] ddd) N-(2-Methyoxypropyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 59), m.p. 179-180° C. (dec).

[0219] fff) N-Ethyl1-(5-(4-pyridyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamidehydrochloride (compound 60), m.p. >227° C. (dec).

[0220] ggg) 1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylicacid methyl ester hydrochloride (compound 61), m.p. >220° C. (dec).

[0221] hhh) N-Ethyl1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamidehydrochloride (compound 62), m.p. >270° C. (dec).

EXAMPLE 10

[0222] The pharmaceutical utility of compounds of this invention areindicated by the following assay for GABAa receptor binding activity.

[0223] Assays are carried out as described in Thomas and Tallman (J.Bio. Chem. 156: 9838-9842, J. Neurosci. 3: 433-440, 1983). Rat corticaltissue is dissected and homogenized in 25 volumes (w/v) of 0.05 M TrisHCl buffer (pH 7.4 at 4° C.). The tissue homogenate is centrifuged inthe cold (4°) at 20,000×g for 20′. The supernatant is decanted and thepellet is rehomogenized in the same volume of buffer and againcentrifuged at 20,000×g. The supernatant is decanted and the pellet isfrozen at −20° C. overnight. The pellet is then thawed and rehomogenizedin 25 volume (original wt/vol) of buffer and the procedure is carriedout twice. The pellet is finally resuspended in 50 volumes (w/vol of0.05 M Tris HCl buffer (pH 7.4 at 40° C.).

[0224] Incubations contain 100 ml of tissue homogenate, 100 ml ofradioligand 0.5 nM (³H-RO15-1788 [³H-Flumazenil] specific activity 80Ci/mmol), drug or blocker and buffer to a total volume of 500 ml.Incubations are carried for 30 min at 4° C. then are rapidly filteredthrough GFB filters to separate free and bound ligand. Filters arewashed twice with fresh 0.05 M Tris HCl buffer (pH 7.4 at 4° C.) andcounted in a liquid scintillation counter. 1.0 mM diazepam is added tosome tubes to determine nonspecific binding. Data are collected intriplicate determinations, averaged and % inhibition of total specificbinding is calculated. Total Specific Binding=Total−Nonspecific. In somecases, the amounts of unlabeled drugs is varied and total displacementcurves of binding are carried out. Data are converted to IC₅₀ or K_(i).The Ki of the compounds in this invention are less than 1 μM.

EXAMPLE 11

[0225] In addition, the following assay may be used to determine if thecompounds of the invention are agonists, antagonists, or inverseagonists, and, therefore, their specific pharmaceutical utility. Thefollowing assay can be employed to determine specific GABAa receptoractivity.

[0226] Assays are carried out as described in White and Gurley(NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling,and Gregory (Receptors and Channels 3: 1-5, 1995) with modifications.Xenopus Laevis oocytes are enzymatically isolated and injected withnon-polyadenylated cRNA mixed in a ratio of 4:1:4 for human derived α,β, and γ subunits, respectively. For each subunit combination,sufficient message is injected to result in current amplitudes of >10 nAwhen 1 μM GABA is applied.

[0227] Electrophysiological recordings are carried out using the twoelectrode voltage-clamp technique at a membrane holding potential of −70mV.

[0228] Compounds are evaluated against a GABA concentration that evokes<10% of the maximal evokable GABA current. Each oocyte is exposed toincreasing concentrations of compound in order to evaluate aconcentration/effect relationship. Compound efficacy is expressed as apercent-change in current amplitude: 100*((Ic/I)−1), where Ic is theGABA evoked current amplitude observed in the presence of compound and Iis the GABA evoked current amplitude observed in the absence ofcompound.

[0229] Specificity of a compound for the Ro15-1788 site is determinedfollowing completion of the concentration/effect curve. After washingthe oocyte sufficiently to remove previously applied compound, theoocyte is exposed to GABA+1 μM Ro15-1788, followed by exposure to GABA+1μM Ro15-1788+compound. Percent change due to addition of compound iscalculated as described above. Any percent change observed in thepresence of Ro15-1788 is subtracted from the percent changes in currentamplitude observed in the absence of 1 μM Ro15-1788. These net valuesare used for the calculation of average efficacy and EC₅₀ values.

[0230] To evaluate average efficacy and EC₅₀ values, theconcentration/effect data are averaged across cells and fit to thelogistic equation. Average values are reported as mean±standard error.

[0231] The invention and the manner and process of making and using it,are now described in such full, clear, concise and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

What is claimed is:
 1. A compound of formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: n is0 or an integer of from 1-3; X is CH, nitrogen, or oxygen; Z is anelectron pair when X is oxygen; Z is hydrogen; Z is aryl, optionallysubstituted with one or two groups independently selected from loweralkyl, lower alkoxy, or halogen; or Z is

where Y is oxygen or sulfur; R is lower alkyl, hydroxy, lower alkoxy,hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each of which ismono or disubstituted independently with halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; R is amino optionally substituted withone or two groups independently selected from lower alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;heteroaryl, arylalkyl or heteroarylalkyl, optionally substituted withone or two groups independently selected from halogen, thio, hydroxyl,lower alkyl, lower alkoxy, or amino; or a carbocyclic group having from3-7 member atoms, where up to two of which atoms are optionally heteroatoms selected from oxygen and nitrogen and where any member of thecarbocyclic group is optionally substituted with halogen, lower alkyl orlower alkoxy; or R is a carbocyclic group having from 3-7 member atoms,where up to three of which members are optionally hetero atoms selectedfrom oxygen and nitrogen and where any member of the carbocyclic groupis optionally substituted with halogen, lower alkyl, or lower alkoxy; Aand B are the same or different and represent hydrogen, or lower alkyl;the C ring represents a thiophene, pyridine, or pyrimidine ring; and Wis aryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each ofwhich may be mono or disubstituted independently with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl portion is lower alkyl.
 2. A compound of the formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: n is0 or an integer of from 1-3; X is CH, nitrogen, or oxygen; Z is anelectron pair when X is oxygen; Z is hydrogen; Z is aryl optionallysubstituted with one or two groups independently selected from loweralkyl, lower alkoxy, or halogen; or Z is

where Y is oxygen or sulfur; R is lower alkyl, hydroxy, lower alkoxy,hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each of which ismono or disubstituted independently with halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; R is amino, optionally substituted withone or two groups independently selected from lower alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;heteroaryl, arylalkyl or heteroarylalkyl, optionally substituted withone or two groups independently selected from halogen, thio, hydroxyl,lower alkyl, lower alkoxy, or amino; or a carbocyclic group having from3-7 members, where up to two of which members are optionally heteroatoms selected from oxygen and nitrogen and where any member of thecarbocyclic group is optionally substituted with halogen, lower alkyl orlower alkoxy; or R is a carbocyclic group having from 3-7 members, whereup to three of which members are optionally hetero atoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isoptionally substituted with halogen, lower alkyl, or lower alkoxy; A andB are the same or different and represent hydrogen, or lower alkyl; andW is aryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each ofwhich may be mono or disubstituted independently with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl portion is lower alkyl.
 3. A compound of the formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: n is0 or an integer of from 1-3; X is CH, nitrogen, or oxygen; Z is anelectron pair when X is oxygen; Z is hydrogen; Z is aryl, optionallysubstituted with one or two groups independently selected from loweralkyl, lower alkoxy, or halogen; or Z is

where Y is oxygen or sulfur; R is lower alkyl, hydroxy, lower alkoxy,hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each of which ismono or disubstituted independently with halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; R is amino, optionally substituted withone or two groups independently selected from lower alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;heteroaryl, arylalkyl or heteroarylalkyl, optionally substituted withone or two groups independently selected from halogen, thio, hydroxyl,lower alkyl, lower alkoxy, or amino; or a carbocyclic group having from3-7 members, where up to two of which members are optionally heteroatoms selected from oxygen and nitrogen and where any member of thecarbocyclic group is optionally substituted with halogen, lower alkyl orlower alkoxy; or R is a carbocyclic group having from 3-7 members, whereup to three of which members are optionally hetero atoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isoptionally substituted with halogen, lower alkyl, or lower alkoxy; A andB are the same or different and represent hydrogen, or lower alkyl; andW is aryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each ofwhich may be mono or disubstituted independently with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl portion is lower alkyl.
 4. A compound of the formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: X isCH, nitrogen, or oxygen; Z is an electron pair when X is oxygen; Z ishydrogen; Z is aryl, optionally substituted with one or two groupsindependently selected from lower alkyl, lower alkoxy, or halogen; or Zis

where Y is oxygen or sulfur; R is lower alkyl, hydroxy, lower alkoxy,hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each of which ismono or disubstituted independently with halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; R is amino, optionally substituted withone or two groups independently selected from lower alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;heteroaryl, arylalkyl or heteroarylalkyl, optionally substituted withone or two groups independently selected from halogen, thio, hydroxyl,lower alkyl, lower alkoxy, or amino; or a carbocyclic group having from3-7 members, where up to two of which members are optionally heteroatoms selected from oxygen and nitrogen and where any member of thecarbocyclic group is optionally substituted with halogen, lower alkyl orlower alkoxy; or R is a carbocyclic group having from 3-7 members, whereup to three of which members are optionally hetero atoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isoptionally substituted with halogen, lower alkyl, or lower alkoxy; and Wis aryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each ofwhich may be mono or disubstituted independently with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl portion is lower alkyl.
 5. A compound according to claim 1 of theformula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: X isCH, nitrogen, or oxygen; Z is an electron pair when X is oxygen; Z ishydrogen; Z is aryl, optionally substituted with one or two groupsindependently selected from lower alkyl, lower alkoxy, or halogen; or Zis

where Y is oxygen or sulfur; R is lower alkyl, hydroxy, lower alkoxy,hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each of which ismono or disubstituted independently with halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; R is amino, optionally substituted withone or two groups independently selected from lower alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;heteroaryl, arylalkyl or heteroarylalkyl, optionally substituted withone or two groups independently selected from halogen, thio, hydroxyl,lower alkyl, lower alkoxy, or amino; or a carbocyclic group having from3-7 members, where up to two of which members are optionally heteroatoms selected from oxygen and nitrogen and where any member of thecarbocyclic group is optionally substituted with halogen, lower alkyl orlower alkoxy; or R is a carbocyclic group having from 3-7 members, whereup to three of which members are optionally hetero atoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isoptionally substituted with halogen, lower alkyl, or lower alkoxy; and Wis aryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each ofwhich may be mono or disubstituted independently with-halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl portion is lower alkyl.
 6. A compound according to claim 1 of theformula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: A,B, C, and D are independently CR₁ or nitrogen, provided that at leastone but not more than two of A, B, C, and D are nitrogen simultaneously;R₁ is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy,hydroxyalkyl, aminoalkyl, alkoxyalkyl, thio, or arylalkyl; X is CH,nitrogen, or oxygen; Z is an electron pair when X is oxygen; Z ishydrogen; Z is aryl, optionally substituted with one or two groupsindependently selected from lower alkyl, lower alkoxy, or halogen; or Zis

where Y is oxygen or sulfur; R is lower alkyl, hydroxy, lower alkoxy,hydroxyalkyl, or aminoalkyl; R is aryl or heteroaryl, each of which ismono or disubstituted independently with halogen, thio, hydroxyl, loweralkyl, lower alkoxy, or amino; R is amino, optionally substituted withone or two groups independently selected from lower alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;heteroaryl, arylalkyl or heteroarylalkyl, optionally substituted withone or two groups independently selected from halogen, thio, hydroxyl,lower alkyl, lower alkoxy, or amino; or a carbocyclic group having from3-7 members, where up to two of which members are optionally heteroatoms selected from oxygen and nitrogen and where any member of thecarbocyclic group is optionally substituted with halogen, lower alkyl orlower alkoxy; or R is a carbocyclic group having from 3-7 members, whereup to three of which members are optionally hetero atoms selected fromoxygen and nitrogen and where any member of the carbocyclic group isoptionally substituted with halogen, lower alkyl, or lower alkoxy; and Wis aryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each ofwhich may be mono or disubstituted independently with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl portion is lower alkyl.
 7. A compound according to claim 1 of theformula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: X isCH, or nitrogen; W is aryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or4-pyridyl, each of which may be mono or disubstituted independently withhalogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- ordialkylamino where each alkyl portion is lower alkyl; and R₂ and R₃ arethe same or different and represent hydrogen, lower alkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, haloalky, or amidoalkyl; aryl, arylalkyl,heteroaryl, or heteroarylalkyl optionally substituted with one or twogroups independently selected from halogen, thio, hydroxyl, lower alkyl,lower alkoxy, or amino; or a carbocyclic or carbocyclic(C₁-C₆)alkylgroup having from 3-7 members in the carbocyclic portion, where up totwo of which members are optionally hetero atoms selected from oxygenand nitrogen and where any member of the carbocyclic group is optionallysubstituted with halogen, lower alkyl or lower alkoxy.
 8. A compoundaccording to claim 1 of the formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: X isCH, or nitrogen; W is aryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or4-pyridyl, each of which may be mono or disubstituted independently withhalogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- ordialkylamino where each alkyl portion is lower alkyl; and R₂ and R₃ arethe same or different and represent hydrogen, lower alkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, haloalky, or amidoalkyl; aryl, arylalkyl,heteroaryl, or heteroarylalkyl optionally substituted with one or twogroups independently selected from halogen, thio, hydroxyl, lower alkyl,lower alkoxy, or amino; or a carbocyclic or carbocyclic(C₁-C₆)alkylgroup having from 3-7 members in the carbocyclic portion, where up totwo of which members are optionally hetero atoms selected from oxygenand nitrogen and where any member of the carbocyclic group is optionallysubstituted with halogen, lower alkyl or lower alkoxy.
 9. A compoundaccording to claim 1 of the formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: A,B, C, and D are independently CR₁ or nitrogen, provided that no morethan two of A, B, C, and D are nitrogen simultaneously; R₁ is hydrogen,lower alkyl, lower alkoxy, halogen, hydroxy, hydroxyalkyl, aminoalkyl,alkoxyalkyl, thio, or arylalkyl; X is CH, or nitrogen; W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which maybe mono or disubstituted independently with halogen, hydroxyl, loweralkyl, lower alkoxy, amino, or mono- or dialkylamino where each alkylportion is lower alkyl; and R₂ and R₃ are the same or different andrepresent hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalky, or amidoalkyl; aryl, arylalkyl, heteroaryl, or heteroarylalkyloptionally substituted with one or two groups independently selectedfrom halogen, thio, hydroxyl, lower alkyl, lower alkoxy, or amino; or acarbocyclic or carbocyclic(C₁-C₆)alkyl group having from 3-7 members inthe carbocyclic portion, where up to two of which members are optionallyhetero atoms selected from oxygen and nitrogen and where any member ofthe carbocyclic group is optionally substituted with halogen, loweralkyl or lower alkoxy.
 10. A compound according to claim 1 of theformula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: X isCH, or nitrogen; R is lower alkyl, hydroxy, lower alkoxy, hydroxyalky,or aminoalky; R is aryl, arylalkyl, heteroaryl, or heteroarylalkly,optionally substituted with one or two groups independently selectedfrom halogen, thio, hydroxyl, lower alkyl, lower alkoxy, or amino; or Ris a carbocyclic group having from 3-7 members, where up to three ofwhich members are optionally hetero atoms selected from oxygen andnitrogen and where any member of the carbocyclic group is optionallysubstituted with halogen, lower alkyl, or lower alkoxy; and W is aryl,heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which maybe mono or disubstituted independently with halogen, hydroxyl, loweralkyl, lower alkoxy, amino, or mono- or dialkylamino where each alkylportion is lower alkyl.
 11. A compound according to claim 1 of theformula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: W isaryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each ofwhich may be mono or disubstituted independently with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl portion is lower alkyl; Z is hydrogen; Z is aryl, optionallysubstituted with one or two groups selected from lower alkyl, loweralkoxy, or halogen; or Z is

where Y is oxygen or sulfur; R is lower alkyl, hydroxy, lower alkoxy,hydroxyalky, or aminoalky; R is aryl, arylalkyl, heteroaryl, orheteroarylalkly, optionally substituted with one or two groupsindependently selected from halogen, thio, hydroxyl, lower alkyl, loweralkoxy, or amino; R is amino, optionally substituted with one or twogroups selected from lower alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,haloalkyl, hydroxy, aminoalkyl, amidoalkyl, heteroaryl, or a carbocyclicgroup having from 3-7 members atoms, where up to two of which membersare optionally hetero atoms selected from oxygen and nitrogen and whereany member of the carbocyclic group is optionally substituted withhalogen, lower alkyl or lower alkoxy; or R is a carbocyclic group havingfrom 3-7 members, where up to three of which members are optionallyhetero atoms selected from oxygen and nitrogen and where any member ofthe carbocyclic group is optionally substituted with halogen, loweralkyl, or lower alkoxy.
 12. A compound according to claim 1 of theformula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: X isCH, or nitrogen; W is aryl, heteroaryl, 2- or 3-thienyl, or 2-, 3-, or4-pyridyl, each of which may be mono or disubstituted independently withhalogen, hydroxyl, lower alkyl, lower alkoxy, amino, or mono- ordialkylamino where each alkyl portion is lower alkyl; and R2 and R3 arethe same or different and represent hydrogen, lower alkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, haloalky, or amidoalkyl; aryl, arylalkyl,heteroaryl, or heteroarylalkyl optionally substituted with one or twogroups independently selected from halogen, thio, hydroxyl, lower alkyl,lower alkoxy, or amino; or a carbocyclic or carbocyclic(C₁-C₆)alkylgroup having from 3-7 members in the carbocyclic portion, where up totwo of which members are optionally hetero atoms selected from oxygenand nitrogen and where any member of the carbocyclic group is optionallysubstituted with halogen, lower alkyl or lower alkoxy.
 13. A compoundaccording to claim 1 which is selected from N-Ethyl1-(6-phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide; N-Methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;1-(5-(2-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-4-Picolyl-1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Hydroxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;4-Fluorophenyl-1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl))-4-piperazine;N-Methylhexahydro-4-(5-phenylthieno[3,2-b]pyridin-7-yl)-(1H-1,4-diazepine)-1-carboxamide;and 4-(5-Phenylthieno[3,2-b]pyridin-7-yl)morpholine.
 14. A compoundaccording to claim 1 which is selected from1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-(1H-1,4-diazepine);N-Ethylhexahydro-4-(5-phenylthieno[3,2-b]pyridin-7-yl)-(1H-1,4-diazepine)-1-carboxamide;N-Ethyl 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;4-Pyridinylcarbonyl-1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl))-4-piperazine;N-Ethyl1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;N-n-Propyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;N-i-Propyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;and N-n-Butyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide.15. A compound according to claim 1 which is selected fromN-(3-Chloro-n-Propyl)1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;N-Ethyl1-(5-(4-fulorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperazinecarboxamide;N-Ethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperazinecarbothioamide;1-(2-Phenyl-1,5-naphthyridin-4-yl)-4-piperidinecarboxylic acid ethylester; N-Ethyl1-(2-phenyl-1,5-naphthyridin-4-yl)-4-piperidinecarboxamide; N-Methyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; N-Propyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; and1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide.
 16. Acompound according to claim 1 which is selected from N-t-Butyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; N-n-Butyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Cyclopropyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Cyclopentyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Aminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Ethylaminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Dimethylaminoethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; andN-Glycinamidyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide.
 17. Acompound according to claim 1 which is selected from N-(2-Hydroxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Methoxyethyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(3-Methoxypropyl)1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; N-Benzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-2-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-3-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-4-Fluorobenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide; andN-4-Methylbenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide.
 18. Acompound according to claim 1 which is selected from N-4-Ethoxybenzyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-4-Pyridylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-2-Thiophenylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-2-Tetrahydrofuranylmethyl1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylic acid ethylester; 1-(5-Phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxylicacid;1-(5-(3-Methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;and N-Ethyl1-(5-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide.19. A compound according to claim 1 which is selected from1-(5-(4-Ethoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-2-Pyridinylmethyl1-(5-(4-ethoxyphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;1-(5-(4-Fluorolphenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Methyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Ethyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Propyl1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Aminoethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;and N-(2-Dimethylaminoethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxyamid.20. A compound according to claim 1 which is selected fromN-(2-Hydroxyethyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-(2-Methyoxypropyl)1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;N-Ethyl1-(5-(4-pyridyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide;1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxylic acid methylester; N-Ethyl1-(6-Phenylthieno[2,3-b]pyridin-4-yl)-4-piperidinecarboxamidehydrochloride; 5-(4-Fluorophenyl)-7-[4-(1H-imidazol-2-yl)-1-piperidinylthieno[3,2-b]pyridine;1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide;and5-(4-Fluorophenyl)-7-[4-(1H-1,2,4-triazol-3-yl)-1-piperidinyl]thieno[3,2-b]pyridine.